1. Field of the Invention
The present invention relates to treatment for lowering intraocular pressure and to compounds for use in such treatments. More particularly, the present invention relates to the use of compounds with serotonergic 5-HT5-HT2 agonist activity to lower intraocular pressure (IOP), treat glaucoma, and to provide neuroprotection.
2. Description of the Related Art
Serotonin (5-hydroxy tryptamine; 5-HT5-HT) is an endogenous biogenic amine with a well defined neurotransmitter function in many tissues of the body including the eye [Zifa and Fillion 1992; Hoyer et al. 1994; Tobin et al. 1988].
5-HT is known to interact with at least seven major 5-HT receptors (5-HT1–5-HT7) and additional subtypes within these families to initiate intracellular biochemical events such as stimulation of second messengers (e.g. cAMP, inositol trisphosphate) eventually leading to the final biological response, for example, tissue contraction or hormone release, etc. [Hoyer et al. 1994; Martin et al. 1998]. Receptor subtypes within the 5-HT1 family are negatively coupled to adenylyl cyclase (AC) and cause inhibition of cAMP production, while 5-HT4, 5-HT6, and 5-HT7 receptors are positively coupled to AC and thus stimulate cAMP production when activated by 5-HT [Martin et al. 1998]. The receptors in the 5-HT2 family are positively coupled to phospholipase C (PLC) and thus generate inositol phosphates and mobilize intracellular calcium when activated to mediate the effects of 5-HT. The 5-HT3 receptor is unique in that it couples to an ion channel which gates sodium, potassium, and calcium [Hoyer et al. 1994].
The human and animal 5-HT7 receptor has only recently been cloned, expressed, and shown to be present in various brain areas and peripheral tissues [Eglen et al. 1997]. Recent studies have shown there to be four splice variants of the 5-HT7 receptor [Heidmann et al. 1997]. It has been proposed that the 5-HT7 receptor may be involved in the pathophysiology of sleep disorders, depression, and other psychiatric disorders [Eglen et al. 1997]. In the periphery, stimulation of 5-HT7 receptors results in relaxation of blood vessels and hence vasodilation [Eglen et al. 1997].
Known compounds exhibiting 5-HT2 agonist activity have typically been designed to treat numerous central nervous system (CNS)-related conditions, particularly the treatment of obesity and depression, by activation of 5-HT2C receptors. Thus, one desired property of known 5-HT2 agonist compounds is that they easily penetrate the blood brain barrier. Compounds possessing the property of penetration into the CNS generally do not contain polar groups.
To treat ocular diseases, it is desirable to administer compositions orally or topically that will remain in the ocular tissues and not cross the blood brain barrier to enter the CNS. What are needed are 5-HT2 agonist compounds that are useful in the treatment of ocular diseases characterized by an elevated intraocular pressure, the treatment of glaucoma and neuroprotection. Such compounds would not have a propensity to cross the blood brain barrier.